Inflammation-induced osteolysis, such as occurs in rheumatoid and psoriatic arthritis, is one of the most common skeletal diseases. Most previous studies focused on the role of inflammatory or immune cytokines on pathogenesis of inflammatory osteolysis. Unfortunately, interrupting cytokines does not completely arrest the bone erosion implying the existence of other critical pathways for bone resorption. In this proposal, we will investigate the pathogenesis of inflammatory bone loss from a totally different angle: inflammation-induced extracellular nucleosides as ligands for the triggering receptor expressed on myeloid cells 2 (TREM2), which is thus a unique receptor linking inflammation, immune function and bone metabolism. Our previous studies demonstrated that the TREM2 pathway is also associated with elevated osteoclastogenesis induced by antiviral nucleoside analogs. TREM2 has been demonstrated to be a costimulatory receptor enhancing RANK-mediated osteoclastogenesis. However, the specific ligand for TREM2 has not yet been identified. We hypothesize that nucleosides may be an endogenous ligand for the TREM2 receptor, because nucleosides potentially link inflammation, immune system and bone metabolism. An abundance of nucleosides is accumulated in the synovial fluid of rheumatoid arthritis (RA) patients. Therefore, our hypothesis is that bone destruction caused by inflammation is mediated through accumulated nucleosides activating the TREM2 pathway that enhances the RANK-dependent osteoclastogenesis. This proposal will elucidate the pathogenesis of inflammatory bone loss at the molecular level. There are two specific aims: Specific Aim I Characterize the osteoclastogenic effects of nucleosides in vivo and in vitro. Part A. Characterize osteoclastogenic effects of nucleosides in mice. Part B. Characterize the anti-osteolytic effect of blocking TREM2 in vitro and in vivo. Specific Aim II Characterize the role of the TREM2 pathway in nucleoside enhanced osteoclastogenesis. Part A. Characterize the binding of nucleosides to the TREM2 receptor. Part B. Determine the effect of nucleosides on the expression of TREM2. Part C. Determine the intracellular signals in the TREM2 pathway stimulated by nucleosides. PROJECT NARRATIVE Inflammation-induced osteolysis, such as occurs in rheumatoid and psoriatic arthritis, is one of the most common skeletal diseases. This proposal will investigate the pathogenic role and molecular mechanism of abundant nucleosides released from inflammatory pathogens or damaged host cells in inflammation-induced bone destruction. These studies will provide a new therapeutic target for inflammation-induced bone-joint destruction.